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Precedia/Multispecific antibodies/Tox package

What tox package did approved multispecifics have, from first-in-human to approval?

From the FDA and EMA reviews of all 18 approved multispecifics. Each answer links to the regulator's own sentence.

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Short answer
5 of 18 ran first-in-human outside the US (where the reviews say so); 10 had a recovery phase in the longest repeat-dose study; 0 finished PPND after the marketing application.
First-in-human: US and ex-US5/18
First-in-human: not stated13/18
Longest repeat-dose: with recovery phase10/18
Longest repeat-dose: no recovery phase2/18
Longest repeat-dose: recovery not stated3/18
Longest repeat-dose: no repeat-dose study3/18
PPND: not conducted18/18
Carcinogenicity: not required18/18

Precedent by precedent

18 approved multispecifics, with the reviewers' own words.

Lunsumio

mosunetuzumab · CD20 x CD3
First-in-human: where
US, Republic of Korea, Canada: dose-escalation part (Group A) of study GO29781 in patients with R/R B-cell NHL
“● Group A (n=33): United States 25 (5), Republic of Korea 7 (2), Canada 1 (1).”
✓ VerifiedEMA assessment report, p. 82Source ↗
Longest repeat-dose study and recovery
26-week GLP cynomolgus monkey study (IV step-up then weekly); recovery phase not stated
“In the pivotal 26-week GLP toxicity study (16-1815), exposure was maintained in 7/7 animals in the 0.5 mg/kg target-dose group, and in 4/7 surviving animals past TK Day 84 in the 0.1 mg/kg group.”
✓ VerifiedEMA assessment report, p. 33Source ↗
PPND / ePPND: when
Monkey EFD/prenatal-postnatal study waived by FDA on weight of evidence
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993). In a written communication from the FDA dated 14 June 2018, the Agency agreed to the waiver request.”
✓ VerifiedFDA multi-discipline review, p. 59Source ↗
Carcinogenicity timing
Not required; none conducted or planned for the oncology indication
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
✓ VerifiedFDA multi-discipline review, p. 59Source ↗

Rybrevant

amivantamab · EGFR x MET
First-in-human: where
US and ex-US (Australia, Canada, China, France, Japan, Korea, Spain, Taiwan, UK): first-in-human dose escalation/expansion in advanced NSCLC
“Ongoing Australia, Canada, China, France, Japan, Republic of Korea, Spain, Taiwan, UK, US 53 Phase 1 First-in-human, openlabel, 2- part, dose escalation and dose expansion, multicenter study Men and women ≥18 years of age with histologically or cytologically confirmed advanced NSCLC”
✓ VerifiedEMA assessment report, p. 60Source ↗
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study, weekly 60 or 120 mg/kg
“Janssen conducted a GLP-compliant 13-week toxicology study in cynomolgus monkeys. Monkeys received intravenous amivantamab once weekly at doses of 0, 60, or 120 mg/kg.”
✓ VerifiedFDA multi-discipline review, p. 37Source ↗
PPND / ePPND: when
Not conducted: fertility and pre-/postnatal development studies not necessary for the BLA in this indication
“fertility and early embryonic development and prenatal and postnatal development studies are not necessary for the submission of a BLA for the proposed indication.”
✓ VerifiedFDA multi-discipline review, p. 61Source ↗
Carcinogenicity timing
Not required (advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
✓ VerifiedFDA multi-discipline review, p. 37Source ↗

Talvey

talquetamab · GPRC5D x CD3
First-in-human: where
US and ex-US (Belgium, France, Germany, Israel, Netherlands, Poland, Korea, Spain): first-in-human dose escalation/expansion
“Study Location: This study was conducted at 47 centers that treated at least 1 participant in Belgium, France, Germany, Israel, the Netherlands, Poland, Republic of Korea, Spain, and the United States.”
✓ VerifiedFDA multi-discipline review, p. 111Source ↗
Longest repeat-dose study and recovery
4-week (weekly x4) IV cynomolgus monkey study with tool molecule JNJ-64024701; no recovery period
“Monkeys were administered JNJ￾64024701 as a once weekly (QW x 4) IV bolus injection (0 [control], 10, or 30 mg/kg), followed by sacrifice and necropsy on Day 29; there was no recovery period.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗
PPND / ePPND: when
Not conducted: monkey EFD or enhanced PPND with talquetamab or tool molecule judged not feasible and uninformative (weight of evidence)
“Based on a weight-of-evidence risk assessment (Mod2.6.6/Sec6.2), an embryo-fetal development or enhanced pre- and postnatal development study in cynomolgus monkeys with talquetamab or the tool molecule would not be feasible nor further inform pregnancy risk to multiple myeloma patients.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗
Carcinogenicity timing
Not required (FDA agrees not warranted)
“We agree that carcinogenicity studies are not warranted to support the approval of BLA 761342.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Tecvayli

teclistamab · BCMA x CD3
First-in-human: where
US and ex-US (Belgium, Canada, France, Germany, Italy, Netherlands, Spain, Sweden, UK): first-in-human study
“Trial Location: This study was conducted at 39 centers that treated at least 1 subject in Belgium (2), Canada (4), France (6), Germany (3), Italy (2), Netherlands (1), Spain (7), Sweden (3), the United Kingdom (3), and the United States (8).”
✓ VerifiedFDA multi-discipline review, p. 73Source ↗
Longest repeat-dose study and recovery
5-week weekly IV cynomolgus monkey study with 8-week recovery
“Monkeys were administered teclistamab (0 [control], 1, 10, or 30 mg/kg/dose, IV) once weekly for five total doses followed by an 8-week recovery period.”
✓ VerifiedFDA multi-discipline review, p. 38Source ↗
PPND / ePPND: when
Not conducted: reproductive and developmental toxicity studies would not be meaningful and are not warranted
“Similarly, reproductive and developmental toxicity studies would not provide meaningful information and are not warranted to support a BLA.”
✓ VerifiedFDA multi-discipline review, p. 38Source ↗
Carcinogenicity timing
Not required; FDA agreed carcinogenicity studies not needed
“We agree that carcinogenicity studies are not needed to support the approval of BLA 761261.”
✓ VerifiedFDA multi-discipline review, p. 46Source ↗

Ziihera

zanidatamab · HER2 x HER2 (biparatopic)
First-in-human: where
North America and South Korea: first-in-human study ZWI-ZW25-101 in HER2-expressing cancers
“Supportive ZWI-ZW25-101 (Phase 1) NCT02892123 N Am (12) S Korea (5) Locally advanced (unresectable) and/or metastatic HER2-expressing cancers”
✓ VerifiedFDA multi-discipline review, p. 65Source ↗
Longest repeat-dose study and recovery
13-week weekly IV GLP cynomolgus monkey study (8-week interim termination) with 8-week recovery
“ZW25: A 13-Week Intravenous Infusion Toxicity Study With an 8-Week Interim Termination in Cynomolgus Monkeys With 8-Week Recovery Periods (GLP).”
✓ VerifiedFDA multi-discipline review, p. 42Source ↗
PPND / ePPND: when
Not conducted: de novo developmental and reproductive toxicity studies not warranted (zanidatamab considered an embryofetal toxicant)
“Jazz proposes that zanidatamab should be considered an embryofetal toxicant. Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
✓ VerifiedFDA multi-discipline review, p. 46Source ↗
Carcinogenicity timing
Not required; FDA: carcinogenicity studies not warranted
“Carcinogenicity studies were not warranted.”
✓ VerifiedFDA multi-discipline review, p. 46Source ↗

Bizengri

zenocutuzumab · HER2 x HER3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
13-week IV cynomolgus monkey study (weekly doses) with 6-week recovery
“In the 13-week repeat-dose toxicology study in monkeys, zenocutuzumab was intravenously administered at 10, 30, and 101 mg/kg once weekly for 13 weeks, followed by a 6-week recovery period.”
✓ VerifiedFDA multi-discipline review, p. 82Source ↗
PPND / ePPND: when
No PPND or other reproductive/developmental studies; literature-based weight-of-evidence assessment instead
“Reproductive and developmental toxicology studies have not been performed. The Sponsor is of the opinion that sufficient data are available in the public domain to assess a hazard to reproduction for MCLA-128”
✓ VerifiedFDA multi-discipline review, p. 85Source ↗
Carcinogenicity timing
Not required; FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this BLA submission.”
✓ VerifiedFDA multi-discipline review, p. 85Source ↗

Blincyto

blinatumomab · CD19 x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
13-week SC mouse study with murine surrogate muS103new, 4-week recovery
“Therefore, in the 13-week repeat-dose toxicology study in mice, BALB/c mice were administered muS103new (0, 1, or 5 mg/kg/day; 0, 2, or 10 mg/kg/day) by subcutaneous injection twice daily with an 8-hour interval between doses for 13 weeks with a 4-week recovery period.”
✓ VerifiedFDA pharmacology/toxicology review, p. 82Source ↗
PPND / ePPND: when
No PPND study; reproductive toxicity limited to mouse EFD with murine surrogate (no reason given)
“Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent”
✓ VerifiedEMA assessment report, p. 32Source ↗
Carcinogenicity timing
Not required for advanced cancer indication (ICH S9)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
✓ VerifiedEMA assessment report, p. 31Source ↗

Columvi

glofitamab · CD20 x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
4-week IV/SC step-up cynomolgus monkey study with 4-week treatment-free period
“RO7082859: A 4-week intravenous and subcutaneous toxicity and toxicokinetic study in Mauritius cynomolgus monkeys followed by a 4-week treatment-free period”
✓ VerifiedFDA multi-discipline review, p. 58Source ↗
PPND / ePPND: when
No PPND or other reproductive animal studies; weight-of-evidence risk assessment instead
“While no animal studies were conducted to assess the reproductive and developmental risks of glofitamab, a weight of evidence (WoE)-based risk assessment report was submitted.”
✓ VerifiedFDA multi-discipline review, p. 41Source ↗
Carcinogenicity timing
Not required: advanced cancer indication (ICH S9)
“Glofitamab is intended for the treatment of patients with advanced cancer. In line with the ICH S9 guideline, no carcinogenicity studies were performed (ICH S9).”
✓ VerifiedFDA multi-discipline review, p. 66Source ↗

Elrexfio

elranatamab · BCMA x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
3-month (13-week) SC cynomolgus monkey study (14 weekly doses), no recovery phase
“Cynomolgus monkeys (3/sex/group, 5-8 years of age, sexually mature, Mauritius origin) were administered elranatamab at 0, 0.3, 3 and 6 mg/kg SC, Q1W for 14 doses. Scheduled necropsy was performed on Day 93; one day after the last dose. A recovery period was not included.”
✓ VerifiedEMA assessment report, p. 41Source ↗
PPND / ePPND: when
No PPND or other DART studies; reproductive organs assessed in monkey studies plus weight-of-evidence assessment
“No reproductive and/or developmental toxicity studies have been conducted with elranatamab. Effects on reproductive organs were assessed in pivotal studies using sexually mature male and female cynomolgus monkeys. Additionally, an integrated weight of evidence assessment was conducted to evaluate the potential for elranatamab to elicit developmental effects.”
✓ VerifiedFDA multi-discipline review, p. 65Source ↗
Carcinogenicity timing
Not required for advanced cancer and protein-based biotherapeutics
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
✓ VerifiedEMA assessment report, p. 43Source ↗

Epkinly

epcoritamab · CD20 x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
5-week IV/SC cynomolgus monkey study with 6-week recovery
“Study: A 5-Week Toxicity Study of GEN3013 by Intravenous Infusion and Subcutaneous Injection in Cynomolgus Monkeys with Bioavailability, Local Tolerance, and a 6 Week Recovery Period”
✓ VerifiedFDA multi-discipline review, p. 53Source ↗
PPND / ePPND: when
No PPND study, per ICH S9 (advanced cancer); EFD also waived
“Per ICH S9, studies of fertility and early embryonic development, and pre- and postnatal toxicity were not conducted.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗
Carcinogenicity timing
Not required; FDA agreed carcinogenicity studies not needed for approval
“We agree that carcinogenicity studies are not needed to support the approval of BLA 761324.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Hemlibra

emicizumab · FIXa x FX
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
26-week SC cynomolgus monkey study (weekly) with 13-week recovery
“A 26-week intermittent dose (once weekly, 27 doses) subcutaneous administration toxicity study of CH5534262 in mature cynomolgus monkeysfollowed by a 13-week recovery period / Study report no. 1060134”
✓ VerifiedFDA multi-discipline review, p. 39Source ↗
PPND / ePPND: when
No PPND or other DART studies: hemophilia A is X-linked recessive (patients mostly male)
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
✓ VerifiedFDA multi-discipline review, p. 42Source ↗
Carcinogenicity timing
Not required; carcinogenicity assessment accepted and ECAC agreed no studies needed
“The ECAC agreed with the Division that there was no need for additional nonclinical carcinogenicity studies for emicizumab on August 7, 2015.”
✓ VerifiedFDA multi-discipline review, p. 155Source ↗

Imdelltra

tarlatamab · DLL3 x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
3-month (13-week) weekly IV cynomolgus monkey study; recovery phase not stated
“Tarlatamab: 3-Month Intravenous Toxicology Study in the Cynomolgus Monkey / Study Number: 122516 /eCTD location: Module 4.2.3.2 Key Drug-related Adverse Findings No adverse effects on any toxicology or safety pharmacology parameters evaluated at up to the high dose of 4500 µg/kg weekly for 3 months.”
✓ VerifiedFDA multi-discipline review, p. 67Source ↗
PPND / ePPND: when
No PPND study; reproduction testing limited to mouse EFD with murine surrogate
“Animal reproduction studies have not been conducted with tarlatamab-dlle. In an embryo-fetal developmental toxicity study, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis.”
✓ VerifiedFDA review, p. 35Source ↗
Carcinogenicity timing
Not required (none conducted or planned per ICH S9; FDA agreed)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010). The FDA’s Assessment: The FDA agrees.”
✓ VerifiedFDA multi-discipline review, p. 73Source ↗

Kimmtrak

tebentafusp · CD3 x gp100 (TCR fusion)
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
No repeat-dose study (human HLA-restricted; all toxicology in vitro)
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro.”
✓ VerifiedFDA multi-discipline review, p. 44Source ↗
PPND / ePPND: when
No PPND or other in vivo DART studies (no relevant species); weight-of-evidence assessment
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”
✓ VerifiedFDA multi-discipline review, p. 46Source ↗
Carcinogenicity timing
Not required for the proposed indication
“The FDA’s Assessment: Carcinogenicity studies were not warranted for the proposed indication.”
✓ VerifiedFDA multi-discipline review, p. 46Source ↗

Korjuny

catumaxomab · EpCAM x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
No repeat-dose toxicity study (no appropriate animal species); single/escalating-dose studies only
“Repeat-dose toxicity studies have not been performed with catumaxomab due to the lack of an appropriate animal species.”
✓ VerifiedEMA assessment report, p. 38Source ↗
PPND / ePPND: when
No PPND or other DART studies: no appropriate species, late-stage malignancy population
“Studies to investigate reproductive and developmental toxicity have not been performed due to the lack of an appropriate animal species, the intended patient population with late-stage malignant disease.”
✓ VerifiedEMA assessment report, p. 38Source ↗
Carcinogenicity timing
Not required (inappropriate for biotechnology-derived products per ICH S6)
“Standard carcinogenicity studies are generally inappropriate for biotechnology-derived pharmaceuticals according to ICH S6.”
✓ VerifiedEMA assessment report, p. 38Source ↗

Lynozyfic

linvoseltamab · BCMA x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
9- or 14-week IV cynomolgus monkey study with 13-week recovery
“For the remaining animals the study was then divided into a 9-week (20 mg/kg group) or 14-week (1 and 5 mg/kg groups) repeat-dose study, each followed by a 13-week recovery phase.”
✓ VerifiedFDA multi-discipline review, p. 72Source ↗
PPND / ePPND: when
Not conducted: no animal reproductive or developmental toxicity studies; immune activation may compromise pregnancy maintenance
“No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab. Linvoseltamab causes T cell activation and cytokine release; immune activation may compromise pregnancy maintenance.”
✓ VerifiedEMA assessment report, p. 37Source ↗
Carcinogenicity timing
Not required (ICH S9)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
✓ VerifiedEMA assessment report, p. 33Source ↗

Ordspono

odronextamab · CD20 x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
16-week weekly IV cynomolgus monkey GLP study with 14-week recovery
“following once weekly IV infusions of 0.1 and 1 mg/kg for 16 weeks (total of 17 doses) with a 14-week recovery period.”
✓ VerifiedEMA assessment report, p. 34Source ↗
PPND / ePPND: when
Not conducted: embryo-fetal studies expected to have limited value for patients with advanced cancer
“Embryo-fetal developmental toxicology studies with odronextamab were not conducted as such studies are expected to have limited value in further understanding and communicating risks to patients with advanced cancer.”
✓ VerifiedEMA assessment report, p. 35Source ↗
Carcinogenicity timing
Not required (ICH S9)
“As odronextamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with odronextamab, consistent with ICH guideline S9 on non-clinical evaluation for anticancer pharmaceuticals”
✓ VerifiedEMA assessment report, p. 35Source ↗

Removab

catumaxomab · EpCAM x CD3
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
No repeat-dose toxicology study (no relevant species)
“The most notable consequence of the inability to find a relevant species is that the present application does not contain repeated dose toxicology studies of catumaxomab.”
✓ VerifiedEMA assessment report, p. 10Source ↗
PPND / ePPND: when
Not conducted: reproductive and developmental toxicity studies not submitted
“Reproductive and developmental toxicity studies have not been submitted.”
✓ VerifiedEMA assessment report, p. 14Source ↗
Carcinogenicity timing
Not required: absence of studies accepted given no suitable animal models
“The absence of many non￾clinical studies is considered acceptable for an antibody, given the absence of suitable animal models.”
✓ VerifiedEMA assessment report, p. 15Source ↗

Vabysmo

faricimab · VEGF-A x Ang-2
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
26-week once-monthly IVT cynomolgus monkey study with 13-week recovery
“Study # 8292406, 26-Week Partial Ascending-Dose Toxicity and Toxicokinetic Study Following Once Monthly Intravitreous Injections in Cynomolgus Monkeys with a 13-Week Recovery”
✓ VerifiedFDA pharmacology/toxicology review, p. 17Source ↗
PPND / ePPND: when
PPND in cynomolgus monkey not conducted: ADA formation and exposure loss prevent sufficient systemic exposure
“A pre- and postnatal development study could not be conducted in cynomolgus monkeys due to ADA formation and exposure loss observed in general toxicology studies preventing sufficient systemic exposure with faricimab in such a study.”
✓ VerifiedEMA assessment report, p. 34Source ↗
Carcinogenicity timing
Not required; weight of evidence does not suggest carcinogenic potential
“No standard rodent carcinogenicity studies have been conducted as faricimab is not fully cross-reactive in rodents. The intended anti-angiogenic effects of faricimab and the weight of evidence do not suggest a carcinogenic potential of faricimab.”
✓ VerifiedEMA assessment report, p. 34Source ↗